Several genes related to the neurotransmission of dopamine, including DRD4, SLC6A3 and SNAP-25, have been associated with ADHD via meta-analyses and animal models. Yet, little is known about how these genes act on the brain to produce meaningful phenotypic variation in individuals with and without the disorder. Because performance on measures of working memory and interference control is impaired in ADHD samples, familially-linked to the condition and impacted by dopamine function, genetic imaging studies investigating neural networks that support these executive functions are likely to offer further clarification of etiological pathways. The overarching aim of the current project is to use an existing data set to generate hypotheses about the relationship between three ADHD candidate genes (DRD4, SLC6A3 and SNAP-25), neuroimaging measures of working memory and interference control networks, neurocognitive measures of these functions and behavioral symptoms of ADHD. Our specific aims involve 1) examining the association between polymorphic variation across these candidate genes and ADHD neuroimaging phenotypes, 2) including neurocognitive measures in multivariate association tests of neuroimaging phenotypes and these genes, and 3) exploring the relationship of positively associated phenotypes using structural equation models to better understand risk mechanisms that link genes and brain function to cognition and disorder. Subjects are individuals with (N =128) and without (N =68) ADHD who have had genetic, functional and structural neuroimaging, neurocognitive and ADHD symptom data collected as part of other research projects at Mass General Hospital. By exploring genetic, neuroimaging, neurocognitive and symptom data simultaneously in an existing sample, we will generate testable models of pathways from genes to behavior in a comprehensive, cost-efficient and timely manner. This work will lead to improved understanding of the heritable pathophysiology and risk mechanisms underlying ADHD and impaired cognition, which in turn should create new opportunities for prevention, early intervention, therapeutics and diagnostic tests. PUBLIC HEALTH RELEVANCE: DRD4, SLC6A3 and SNAP-25 have been associated with ADHD via meta-analysis and animal models;however, the mechanism by which these genes contribute to variation in neurocognition and behavior is unknown. Structural and functional neuroimaging-based measures of working memory and interference control networks are putative endophenotypes that may shed light on the risk mechanisms associated with these genes. This project will examine the relationship between these genes, neuroimaging and neurocognition measures and ADHD symptoms in individuals with and without the disorder. Our goal is to generate hypotheses regarding pathways from genes to brain to behavior. Improved understanding of the heritable pathophysiology of ADHD and the genetically-mediated neurodevelopmental risk mechanisms that lead to poor cognitive function have important clinical and public health implications. Such knowledge could uncover new targets for therapeutics and diagnostic tests and help focus limited societal resources on those at risk for ADHD or cognitive impairment.